Thrombotic disorders are characterized by formation of a thrombus that obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow downstream. Thrombotic disorders are a major cause of death in the industrialized world.
Presently there are numerous antithrombotic drugs which are widely available, they also called as Direct Thrombin Inhibitors (DTIs) which are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. In another exemplary embodiment, the DTI is univalent. In another exemplary embodiment, the DTI is bivalent. In an exemplary embodiment, the DTI is a member selected from hirudin, bivalirudin (IV), lepirudin, desirudin, argatroban (IV), dabigatran, dabigatran etexilate (oral formulation), melagatran, ximelagatran (oral formulation but liver complications) and prodrugs thereof.
Dabigatran etexilate (Formula l), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-vascular atrial fibrilitaion.

The methane sulphonic acid addition salt of dabigatran etexilate, which is commercially available under the trade name PRADAXA®, is disclosed in EP1870100, also disclosed, pellet composition of dabigatran etexilate mesylate (Formula II). This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core.

Apart from the mesylate salt of dabigatran etexilate, other acid addition salts of the compound are provided in prior art. For example, WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395. These various form of dabigatran etexilate are prepared to facilitate the development of pharmaceutical composition. An active agent should meet some physicochemical requirements in order to be capable of being used in pharmaceutical compositions. These requirements considerably depend on the physicochemical properties of the active agent used in pharmaceutical composition.
However, dabigatran etexilate is associated with side effects. The administration of antithrombotic agents, such as dabigatran etexilate, have been associated with gastrointestinal disorders such as ulcers and gastrointestinal bleeding. In addition, the administration of dabigatran etexilate, may make some patients more susceptible to the ulcerogenic effects of ulcerogenic stimuli. It appears that a major factor contributing to the development of these gastrointestinal disorders is the presence of acid in the stomach and upper small intestine. While the mechanisms associated with ulcers and gastrointestinal bleeding are not entirely known, there are many causes of ulcers, including stress, alcohol irritation, Helicobacter pylori infection, and the side effects of non-steroid anti-inflammatory drugs. Patients in need of long term antithrombotic drug therapy often may interrupt or not receive such therapy due to gastrointestinal disorders, and as a result, patients are deprived of beneficial antithrombotic drug therapy. There is a need for oral pharmaceutical combination formulations to reduce or eliminate the gastrointestinal disorders associated with use of antithrombotic drugs.
Proton pump inhibitors (PPI) are acid labile compounds useful for inhibiting gastric acid secretion. The problems arisen from this acid labile characteristic of these compounds is overcome by providing a formulation that dissolves in the intestines rather than the acidic environment of the stomach.
Using an antacid or an alkaline excipient with a PPI in the formulation is one method used in the art to reduce the acidity of the gastrointestinal environment. Another one is to provide an enteric coating for the composition comprising the acid labile PPI.
It is known in the state of art that the enteric polymers with acidic nature are not compatible with the proton pump inhibitors and the alkaline excipients used in the formulation. To overcome this problem an inert intermediate layer may be introduced, such as in the prior art. In U.S. Pat. No. 4,853,230 and WO 96/24338 enteric coated formulations with an alkaline active ingredient containing core and a separating layer are described.
Another role of the enteric coating is to provide a modified release. The delivery of the active ingredient to specific sites in the gastrointestinal tract is achieved by enteric coatings. These polymers can also prolong or extend the amount of active ingredient released from the dosage form.
Lansoprazole is a proton pump inhibitor (PPI) which inhibits the stomach's production of gastric acids. Lansoprazole is a racemate 1:1-mixture of the enantiomers dexlansoprazole and levolansoprazole. Dexlansoprazole is an enantiomerically pure active ingredient of a commercial drug as a result of the enantiomeric shift.
In prior art, there are many patents including benzimidazoles such as lansoprazole and its R-enantiomer, dexlansoprazole in several different pharmaceutical compositions. Crystal form of R-lansoprazole is described in EP1129088.
One of the active ingredient from the group of PPI, dexlansoprazole is the R-enantiomer of lansoprazole which inhibits gastric acid secretion (a proton pump inhibitor). Its chemical name is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl} sulfinyl]-1H-benzimidazole and its chemical structure is shown in the Formula III.

Delayed release capsule form of dexlansoprazole is in the market and it is administered orally in a therapeutic dose of 30 mg and 60 mg.
As other benzimidazole compounds, dexlansoprazole has also poor stability and is unstable to acidic medium, humidity, light and sensitive to heating. When orally administrated, it may not be able to sufficient activity since it is decomposed by gastric acid and the like. Thus, several problems occur in formulating such compound into oral pharmaceutical dosage forms because of the acidic environmental of the stomach. In particular, it will be rapidly decomposed and change colour under moist conditions or in acidic to neutral aqueous solution.
Another one from the group of PPI is the compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz imidazole, having the generic name omeprazole, and therapeutically acceptable alkaline salts thereof are described in U.S. Pat. No. 4,255,431 to Junggren et al., EP 5129 and EP 124 495, respectively. Omeprazole and structurally similar sulfoxide compounds are known inhibitors of gastric acid secretion and are used as anti-ulcer agents. The sulfur atom of the sulfoxide group in asymmetrically substituted sulfoxides is chiral. Therefore, omeprazole and related sulfoxides exhibit optical isomerism at the sulfur atom of the sulfoxide. In fact, omeprazole exists as a pair of enantiomers; the S (−) enantiomer is referred to as esomeprazole.
Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphonamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion. Its chemical name is (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl]-3H-benzoimidazole and its chemical structure is shown in the Formula IV. Certain salts of single enantiomers of omeprazole and their preparation are disclosed in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation. WO 96/02535 discloses a process for the preparation of the single enantiomers of omeprazole and salts thereof.

Pharmaceutical compositions that include one or more compounds obtained by the process aspect of the invention are also provided. In particular, in one variant, a pharmaceutical composition that includes the amorphous esomeprazole produced as described in U.S. Pat. No. 2004077869. The more preferred oral solid preparation is a tablet. A tablet may be prepared by direct compression, wet granulation, or molding, of the amorphous form of esomeprazole with a carrier and other excipients in a manner known to those skilled in the art. The amorphous form of esomeprazole described U.S. Pat. No. 2004077869 may be formulated into typical disintegrating tablet, or into a controlled or extended release dosage forms. Examples of suitable modified release formulation vehicles are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719. WO 96/01623 discloses suitable tableted dosage forms of for instance magnesium salts R- and S-omeprazole.
As described above, the major factor contributing to the development of gastrointestinal disorders is the presence of acid in the stomach and upper small intestine. Therefore, the main object of the invention is administering to a patient an oral dosage form including a combination of an antithrombotic agent and a proton pump inhibitor which can reduce a major factor contributing to the development of gastrointestinal disorder in patients. According to the main object, the pharmaceutical compositions of this invention is for the prevention gastrointestinal tract from side effects associated with antithrombotic therapy and provide greater antithrombotic effect with the results in a lower incidence of side effects. According to prior inventions dabigatran etexilate in combination with proton pump inhibitors in particular dexlansoprazole or esomeprazole have an additive preventive effect in relief of gastrointestinal disorder and provide greater antithrombotic effect with the results in a lower incidence of side effects.
According to the formulation of the present invention it is desired to provide a dosage form comprising in combination a therapeutically effective amount of an antithrombotic agent, specifically dabigatran and a proton pump inhibitor specifically dexlansoprazole or esomeprazole which overcomes above described problems. The main challenges when combining those molecules in the same pharmaceutical form are:
(a) to guarantee the psycho-chemical compatibility between those different active ingredients and/or between the active ingredients and the excipients used; and
(b) to insure the therapeutical compatibility between those active ingredients regarding their stability characteristics.
When dabigatran etexilate is combined with PPI specifically dexlansoprazole or esomeprazole in order to minimize or prevent the side effects of the dabigatran etexilate, these two drug substances must be released, dissolved and absorbed harmoniously. For the efficiency of the formulation, an easy dissolution of both drug substances at a desired time is an important factor. In order to minimize or prevent the side effects of dabigatran etexilate; it is very important for the molecule, in which the molecule is used in combination with the PPIs to release both drug substances at the desired time.